Metabolism of 3-tert-Butyl-4-hydroxyanisole by Microsomal Fractions and Isolated Rat Hepatocytes

S. W. Cummings, L. S. Crouch, R. A. Prough, G. A.S. Ansari, F. P. Guengerich

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Abstract

3-tert-Butyl-4-hydroxyanisole is oxidatively metabolized in the presence of rat liver microsomes, reduced nicotinamide adenine dinucleotide phosphate, and oxygen to yield fert-butylhydroqui-none, terty birtylquinone, and a polar metabolite(s). In the presence of human and rat liver microsomes or eight purified cytochrome P-450 isozymes reconstituted with NADPH-cytochrome P-450 reductase, this phenolic antioxidant is converted to the oxidoreduction-active metabolite, tert-butytquinone, that can stimulate the NADPH oxidase activities of these preparations by 2-to 7-fold. The rate of formation of each of the metabolites of 3-tert-butyl-4-hydroxyanisole was increased by pretreatment of rats with either 5,6-benzoflavone or phenobarbital. In addition the fert-butylhydroquinone and tert-butylquinone concentrations in solution reached apparent steady-state levels during metabolism; the steady-state concentrations were also increased by various animal pretreatment regimens. Furthermore it was shown that the metabolism of 3-tert-butyl-4-hydroxyanisole yielded material which was covalently bound to protein. In the presence of glutathione the rates of formation of the polar metabolite(s) were enhanced 3- to 4-fold, while covalently bound products were nearly stoichiometrically decreased. The increase in the amount of polar metabolite was due to the formation of a 3-tert-butyl-4-hydroxyanisole-glutathione conjugate. 3-tert-Butyl-4-hydroxyani-sole was also oxidatively metabolized by rat lung microsomes to yield the polar metabofite(s) and fert-butylhydroquinone. The polar metabolite(s), fert-butylquinone, and fert-butylhydro-quinone were also shown to be formed in isolated hepatocyte suspensions. They could be found as either the free hydroqui-none, the sulfate conjugate, the glucuronide conjugate, and polar metabolites, presumedly the 3-tert-butyl-4-hydroxyanisole-glu-tathione conjugate. The total tert-butylhydroquinone concentration attained a steady-state level in a manner similar to that seen with the microsomal suspensions. In addition 3-tert-butyl-4-hy-droxyanisole itself formed sulfate and glucuronide conjugates, the glucuronide being the major product.

Original languageEnglish (US)
Pages (from-to)5617-5624
Number of pages8
JournalCancer Research
Volume45
StatePublished - Nov 1 1985

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Cummings, S. W., Crouch, L. S., Prough, R. A., Ansari, G. A. S., & Guengerich, F. P. (1985). Metabolism of 3-tert-Butyl-4-hydroxyanisole by Microsomal Fractions and Isolated Rat Hepatocytes. Cancer Research, 45, 5617-5624.